Diaryl-pyridyl-imidazole methanes and their production

ABSTRACT

Diaryl-pyridyl-imidazolyl methanes of the formula   AND PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALTS THEREOF, WHEREIN R1 and R2 are the same or different alkyl of 1 to 4 carbon atoms, ARE PRODUCED EITHER BY A. REACTING A (DIALKYLPHENYL-PHENYL-PYRIDYL)-METHANOL OF THE FORMULA   WHEREIN R1 and R2 are as above defined, with thionyl-bis-imidazole in the presence of an inert organic diluent at a temperature of from -20* C to about 150* C; or B. REACTING A (DIALKYLPHENYL-PHENYL-PYRIDYL)-METHYL HALIDE OF THE FORMULA   WHEREIN R1 and R2 are as above defined and Hal is chlorine or bromine, WITH IMIDAZOLE IN THE PRESENCE OF AN ACID BINDING AGENT AT A TEMPERATURE OF FROM 20* C to about 180* C. The diaryl-pyridyl-imidazole methanes of the present invention are useful for their antimycotic activity.

United States Patent n91 Draber et al.

[451 Oct. 7, 1975 DIARYL-PYRlDYL-IMIDAZOLE METHANES AND THEIR PRODUCTION [75] Inventors: Wilfried Draber; Manfred Plempel;

Karl Heinz Buchel, all of Wuppertal, Germany [73] Assignee: Bayer Aktiengesellschafl,

Leverkusen, Germany [22] Filed: June 7, 1973 [2]] App]v No.: 367,849

[30] Foreign Application Priority Data June l5, i972 Germany 2229128 [52] US. Cl.... 260/294.8 R; 260/295 S; 260/296 R; 424/263 [51] Int. CL. C07D 213/32 [58] Field of Search 260/294.8 R, 295 S, 296 R, 260/309 [56] References Cited UNITED STATES PATENTS 3,629,273 l2/l97l Draber et al 260/296 R Primary Examiner-Alan L. Rotman [57] ABSTRACT Diaryl-pyridyl-imidazolyl methanes of the formula and pharmaceutically acceptable non-toxic salts thereof, wherein R and R are the same or different alkyl of l to 4 carbon atoms,

are produced either by a. reacting a (dialkylphenyl-phenyl-pyridyl)-methanol of the formula R and R are as above defined, with thi0nyl-bis-imidazole in the presence of an inert organic diluent at a temperature of from -20 C to about 150 C; or

b. reacting a (dialkylphenyl-phenyl-pyridyl)-methyl halide of the formula (III) wherein R and R are as above defined and Hal is chlorine or bromine,

with imidazole in the presence of an acid binding agent at a temperature of from 20 C to about l80 C.

The diaryl-pyridyl-imidazole methanes of the present invention are useful for their antimycotic activity.

21 Claims, No Drawings DIARYL-PYRlDYL-IMIDAZOLE METHANES AND THEIR PRODUCTION The present invention relates to diarylimidazolylmethane compounds, to processes for their production, pharmaceutical compositions using said compounds as the active ingredient and to methods of treating mycosis in humans and animals which comprises administering said compounds.

More particularly, the present invention relates to diphenyl-pyridyl-imidazolyl methanes containing two alkyl substituents in one of the two phenyl rings.

It is known in the art that certain N-tritylimidazoles are active against plant-pathogenic fungi (US. Pat. No. 3,321,366). It is furthermore known that certain N- tritylimidazoles are active against human-pathogenic fungi such as epidermatophytes and other dermatophytes as well as blastomyces and biphase fungi (Belgian Patent Specification No. 720,80]; US. Pat. Nos. 3,655,899; 3,655,900; 3,657,442; 3,657,445; 3,658,956; 3,660,576; and 3,660,577).

It is also known in the art that mono-substituted diaryl-pyridyl-imidazolyl-methanes such as l-(4- fluorophenyl-phenyl-2-pyridyl)-methyl-imida.zole and 1-( 3-trifluoromethyl-phenyl-phenyl-2-pyridyl )-methylimidazole are useful as antimycotic agents (See German Offenlegungsschriften Nos. 1,770,939 and 2,009,020). However, the activity of those compounds both in vitro and in vivo against dermatophytes and especially against varieties of Trichophyton is generally unsatisfactory. The compounds of the present invention, by contrast, are particularly useful against Trichophyton infections.

The present invention, therefore, is concemed with diaryl-pyridyl-imidazolyl-methanes of the formula and pharmaceutically acceptable nontoxic salts thereof, wherein R and R are the same or different alkyl of l to 4 car- (III) wherein R and R are as above defined and Hal is chloro or bromo, with imidazole in the presence of an acid binding agent at a temperature of from about 20 C to about l C The two processes (a) and (b) of the present invention will hereinafter be referred to as Process Variants (a) and (b) respectively.

As stated above, the compounds of the present invention are active against dermatophytes, especially Trichophyton. It was surprisingly discovered that the l- (dialkylphenyl-pyridyl-phenyl)-methyl-imidazoles of the present invention showed a higher level of activity against dermatophytes, and especially Trichophyton, than 1-(4-fluorophenyl-phenyl-Z-pyridyl)-methyl imidazole and l-( 3-trifluoromethylphenyLphenyl-2- pyridyl)-methyl imidazole, which are, from a purely chemical standpoint, the closest compounds of the prior art. 1

According to one embodiment of the present invention, the pyridyl moiety is linked with the methane carbon atom at the 2-position of the pyridyl ring. According to another embodiment of the present invention, the pyridyl moiety is linked to the methane carbon atom at the 4-position of the pyridyl ring.

According to a further embodiment of the present invention, R and R are preferably each a methyl group.

According to a further embodiment of the present invention, R is preferably in the 2- or 3-position of the phenyl ring. According to a further embodiment of the present invention, R is preferably in the 3-, 4-, 5- or 6- position of the phenyl ring.

According to a further embodiment of the present invention, R and R are in different positions on the phenyl ring.

[f (2,3-dimethy1phenyl-phenyl-Z-pyridyl )-methanol and thionyl-bis-imidazole are used as starting materials, the course of the reaction in Process Variant (a) can be represented by the following equation:

lt" 2 ,3-dimethylphenyl-phenyl-Lpyridyl )-methyl chloride and imidazole are used as the starting materials, the course of the reaction in Process Variant (b) can be represented by the following equation:

The formulae (II) and (Ill) provide a general definition of the starting compounds for the Process Variants (a) and (b). In the formulae (I), (II) and (III), R and R individually and independently of one another represent straight-chain or branched alkyl groups of l to 4 carbon atoms, and at least one of them is preferably methyl; Hal in the formula (Ill) preferably represents a chlorine or bromine atom.

The following alcohols and halides of the formulae (ll) and III) are representative of the starting materials utilivablc according to the present invention:

(3,4-dimcthylphenyl-phcnyl-Z-pyridyl )n1cthyl chloride.

(3 ,4-dimcthylphenyl-phenyl-Z-pyridyl )-methanol,

(3,4-dirnethylphenyl-phcnyl-4-pyri(lyl )-methyl ride,

(3,4-dimcthylphenyl-phenyl-4-pyritlyl )-mcthanol,

(2,3-dimcthylphenyl-phenyl-2-pyridyl)-methyl ride,

chlochlo- (2,3-dimethylphenyl-phenyl-4-pyridyl )-methyl ride,

(2,3-dimethylphenyl-phenyl-2-pyridyl )-methanol,

(2,3-dimethylphenyl-phenyl-4-pyridyl )-methanol,

(2,4-dimethylphenyl-phenyl-2-pyridyl )-methyl ride,

(2,4-dimethylphenyl-phenyl-2-pyridyl )-methanol,

(2,4-dimcthylphenyl-phenyl-4-pyridyl )-methyl ride,

(2 ,4-dimethylphenyl-phenyl-4-pyridyl )-methanol (2,S-dimethylphenyl-phenyl-2-pyridyl )-methyl ride,

(2,5-dimethylphenyl-phenyl-Z-pyridyl )-methanol,

(2,S-dimethylphenyl-phenyl-4-pyridyl )-methyl ride,

(2,S-dimethylphenyl-phenyl4-pyridyl )-methanol (2,o-dimethylphenyl-phenyl-2-pyridyl )-methyl ride and (2,o-dimethylphenyl-phenyl-4-pyridyl )-methanol.

chlochlochlochlochlochlo- The alcohols and halides which can be used as starting materials in the process according to the invention are in part known or can be produced by known methods (see Journal of the American Chemical Society, volume 70, pages 4001-4009 (I948) and volume 79, pages 472-480 I957); Journal of Organic Chemistry, volume 26, pages 4084-4088 (1961); US. Pat. Nos. 3,396,224 and 2,624,739).

The pharmaceutically acceptable non-toxic salts of the present invention are preferably those obtained from such acids as the hydrogen halide acids (for example, hydrochloric acid and hydrobromic acid, especially hydrochloric acid), phosphoric acids, nitric acid, monofunctional and bifunctional carboxylic acids, hydroxycarboxylic acids (for example, acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid), and l,S-naphthalenedisulphonic acid. Thus, the preferred salts, according to the present invention are the hydro chloride, hydrobromide, phosphate, nitrate, carboxyl ates, hydroxycarboxylates, (for example, acetate, maleate, succinate, fumarate, tartrate, citrate, salicylate, sorbate, lactate) and l,5-naphthalene-disulphonate.

In process Variant (a) the diluent is preferably a welldried (preferably anhydrous) organic solvent, which is inert to the reaction. Preferred solvents include hydrocarbons (such as benzene and toluene), chlorinated hydrocarbons (such as chlorobenzene, methylene chloride, chloroform and carbon tetrachloride), ketones (such as acetone and methyl ethyl ketone), ethers (such as petroleum ether, diethyl ether and tetrahydrofurane), nitriles (such as acetonitrile), sulphoxides (such as dimethyl-sulphoxide), and amides (such as dimethylformamide). Anhydrous acetonitrile is particularly preferred as the solvent.

The reaction temperature in Process Variant (a) can be varied within a substantial range of 20 C to l50 C. Advantageously, the reaction is carried out at 0 C to 50 C.

In carrying out Process Variant (a) according to the invention, 1 to 3 moles of thionyl-bis-imidazole are generally used per 1 mol of alcohol of the general formula (ll). A larger excess of thionyl-bis-imidazole is only necessary if a badly dried solvent is employed. The reaction usually takes between I and I0 hours. The reaction product precipitates after partially distilling off the solvent and can be filtered off or isolated in accordance with the customary methods.

In Process Variant (b), polar organic solvents may be used. These include. for example. nitriles (such as acetonitrile), sulphoxides (such as dimethylsulphoxide), formamides (such as dimethyl formamide). ketones (such as acetone). and ethers (such as diethyl ether and tetrahydrofurane). However, the reaction is preferably carried out without diluents.

The reaction of Process Variant (b) is carried out in the presence of an acid-binding agent. Preferably, an appropriate excess of imidazole is used as acid-binding agent. It is, however, also possible to add any other organic acid-binding agents including those usually employed for reactions in which acids are liberated, such as lower tertiary alkylamines and aralkylamines (for example, triethylamine and dimethylbenzylamine). The reaction temperature in Process Variant (b) can be varied within a substantial range of C to l80 C, preferably 50 C to l [0 C.

In carrying out the Process Variant (/7) according to the invention, preferably about l mol of imidazole and about 1 mol of acid-binding agent are employed per 1 mol of the compound of the formula (III). The compound produced can be isolated in accordance with known and customary methods.

The new free diaryl-pyridyl-imidazolyl-methanes of the formula (I) and their salts can be interconverted in any suitable manner. Methods for such interconversion are known in the art.

The following compounds are representative of those of the present invention.

l-( 3.4-dimeth lphcnyl-phenyl-4-pyridyl )-methylimidalolc l.5-naphthalcnudisulphonatc ill The preferred compound of the present invention is l-( 2,3-dimethylphenyl-phenyl-Z-pyridyl )-methylimidazole and salts thereof, especially the hydrochloride salt.

The compounds of the present invention show a broad spectrum of antimycotic activity. They exhibit activity against yeasts such as Candida and Cryptococcus molds such as Aspergillus and Penicillium, and dermatophytes such as Trichophyton, Microsporon and Epidermophyton. The compounds of the present invention are particularly active against dermatophytes of the Trichophyton genus.

According to the present invention, the above com pounds may be administered to both humans and animals. The compounds may be used in both the treatmerit and prohylaxis of dermatomycoses and systemic mycoses caused by Trichophytun mentagrophytes and other varieties of Trichophyton, varieties of MicrosporOn. Epidermophymn floccosum blai'romyces and biphase fungi, as well as molds and the above-mentioned pathogens, and also organic mycoses caused by varieties of Candida, Cryptococcus. Corridioides. Hisroplasma and Blastomvces.

In veterinary medicine the compounds of the present invention may be used, for example, against dermatomycoses, systemic mycoses and organic mycoses, especially those caused by the above-mentioned pathogens.

The present invention also comprises pharmaceutical compositions which contain a major or minor amount, e.g., 99.5 to 0.l percent, and particularly 95.0 to 0.5 percent, of at least one diaryl-pyrimidyl-imidazolyl methane as herein defined in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is nontoxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit form; i.e., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain, one, two, three, four or more single doses, or, alternatively, onehalf, third or fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three or four times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dosage will be from about 500 to 9,000 mg, preferably l ,000 to 5,400 mg. ID to mg/kg and, preferably, 20 to 60 mg/kg would be the preferred daily dosage based on the weight of the recipient. In some instances a sufficient therapeutic effect can be obtained at a lower dose while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees capsules, granulates, suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as, for example, starch, lactose, sucrose, glucose or mannitol. sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants, such as colloidal silica, talc, magnesium stearatc, calcium stearate or solid polyethylene glycol, can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound,

suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection suitably comminuted, with a diluent or base as desuch as an aqueous or oleaginous medium and sterilizscribed above, and optionally, with a binder such as ing the suspension or solution. Alternatively, a meacarboxymethyl cellulose, an alginate. gelatin, or polyvisured amount of the compound is placed in a vial and nyl pyrrolidone, a solution retardant such as paraffin, the vial and its contents are sterilized and sealed. An a resorption accelerator such as a quaternary salt andaccompanying vial or vehicle can be provided for mix- /or an absorption agent such as bentonite, kaolin or di- 10 ing prior to administration. Nontoxic salts and salt solu calcium phosphate. The powder mixture can be granutions can be added to render the injection isotonic. Stalated by wetting with a binder such as syrup, starch bilizers, preservatives and emulsifiers can also be paste, acacia mucilage or solutions of cellulosic or pold ymeric materials and forcing through a screen. As an Rectal administration can be effected utilizing supahe nafive to granuluting the powder mixture can be positories in the compound iS admixed IOW- run through the tablet machine and the resulting impermelting, watersolllble insoluble Solids such as P y fectly formed slugs broken into granules. The granules hy n g y 006011 butler. higher fisterfi for can be lubricated to prevent sticking to the tablet formmpl yri y palmitate, r mixtures h r fing dies by means of the addition of stearic acid, a stea- Topical administration can be effected utilizing solid rate salt, talc or mineral oil. The lubricated mixture is dosage unit forms Such as Powders liquid q' then compressed into tablets. The medicaments can dosage unit forms Such as Solutionsr Suspensions also be combined with free flowing inert carriers and Oimmems, pastes, Creams and The Powders are compressed into tablets directly without going through formulated utilizing such carriers as talc, bentonite, sithe granulating or slugging steps. A clear or opaque licic f q polyamiqe Powder fw the \ikeq q and protective coating consisting of a sealing coat of shelq formulatpns can mule Such Carner5- lac, a coating of sugar or polymeric material and a poldmon to those de scnbedabove as polyethylefle glycol ish com-mg of wax can be provided. Dyestuffs can be vegetable and mineral 0liS, fii.COhO|S such as isop ropaadded to these coatings to distinguish different unit no] and h other exclplems such as lemulslfiersi dosages 3O preservatives, colorants, perfumes and the l ke can also Oral fluids such as solutions, syrups and elixirs can be be present Q TT Can 3150 b6 admm'stered as prepared in dosage unit form so mm a given quantity an aerosol, utilizing the usual propellants such as the contains a predetermined amount of the compound. syrups can be prepared by dissolving the compound in The m crobiological activity of the compounds of the a suitably flavored aqueous sucrose solution while elixpresent Invention are Illustrated by the fonowmg data: irs are prepared through the use of a nontoxic alcoholic A. Determination of the antimycotic action spectrum vehicle. Suspensions can be formulated by dispersing in VitrO by means of the series dilution test the compound in a nontoxic vehicle. Solubilizers and Sabouraudsr milieu d-gprelwe is used as the nutriem emulsifiers such as ethoxylated isostearyl alcohols and substrate for dermatophytes and Aspergmh and mean polyoxyethylene sorbitol esters, preservatives, flavor brothglucoseboumon is used as the the nutrient additives Such as pp or saccharim and the strate for blastomyces. The incubation temperature is like be added- 28 C and the incubation time is 24 to 96 hours.

where pp p dosage unit formulations The experimental results are summarized in Table A administration can be microencapsulated. The formui hi h; lation can also be prepared to prolong or sustain the re- "K compound 1 i 1 (4 f| h h lease as for example by coating or embedding particu- Z-pyridyl)-methylimidazole (see above), and late material in polymers, wax or the like. Known compound 2" is l-(3- Parenteral administration can be effected utilizing trifluoromethylphenyl-phenyl-Z-pyridyl)- liquid dosage unit forms such as sterile solutions and methylimidazole (see above).

TABLE A Minimum Inhibitory Concentration in y/ml of Nutrient Medium Trirlmphyluu Can- Ienicilfinm Aspergillis dirlrl Compound mvnmgrnp/iyIes alhr commune nigcr ('UHS Known Com- 4 4 4 4 pound 1 2 2 2 Known Com- 4 4 4 4 pound 2 2 2 2 Example Nov From Table l:

1 0.5 l 4 1 2 0.5 H] 4 4 3 0.5 l 10 4 4 0.5 4 [U 4 5 0.5 I HI I s 0,5 4 4o 40 7 (1 05 l i 0.1 s l l 4 l TABLE A Continued Minimum Inhibitory Concentration in y/ml of Nutrient Medium B. Antimycotic action of the compounds according to the present invention in animal experiments Quinckeanum Trichophvtosis of white mice The development of the Quinckeanum infection in mice can be completely suppressed with doses of 12.5 mg/kg of body weight, of the active compound from Example 7. given orally twice daily up to the eighth day xylene and 97.2 g (4 mols) of magnesium filings in 1.5

liters of ether, with 549 g (3 mols) of 2- benzoylpyridine, and has a melting point of 129 C.

Table 2 below sets forth compounds representative of the present invention.

of the infection per os. Table 2 Preparative Example (Compound No. 7)

Example Melting Point No, Pyridyl R R in C l 2 'l-CH, 4-01,, 96 2 2 2-CH, 4-CH;| 15s 3 2 2-CH, 6-C'H;I Hydrochloride, I20 4 4- -01, 4-CH I08 5 4- K-CH 4CH I22 6 4 2-01, 5-01,, 129 7 2 2 c|-| 3 CH 151 8 2- 2CH 3-CH; 1,5-Naphthalcnc disulfonatc I68 9 4- 'CH 3-CH3 I54 ll) 4- 3CH 4CH;, 1,5-Naphthalenc disulfonale 28.9 g (0.1 mol) of (2,3-dimethylphcnyl-phenyl-Z- pyridyl )-methanol are dissolved in 200 ml of anhydrous acetonitrile. A solution of thionyl-bis-imidazole prepared from 10.7 ml ((1.15 mol) of thionyl chloride and 40.7 g (0.6 mol) of imidazole at 0 to 5 C is added dropwise thereto, under reflux cooling. The reaction is left to proceed overnight at room temperature and is completed by boiling for one hour under reflux.

To isolate the resulting imidazole compound, the excess solvent is distilled off in vacuo, the residue is treated with water, the mixture is extracted with ether and the resulting ether solution is briefly boiled up with active charcoal. After filtration, the solution is dried over sodium sulphate and the solvent is distilled off. The resulting oily residue is triturated with pentane and thereafter crystallizes throughout. Filtration yields 10.5 g (31 percent of theory) of l-(2,3-dimethylphenylphenyl-Z-pyridyl)-methyl-imidazole of melting point 15 1 C.

The (2, 3-dimethylphenyl-phenyl-Zpyridyl methanol used as the starting product is obtained in a yield of 580 g (67 percent of theory) by reaction of 2,3-dimethylphenylmagnesium bromide, which was manufactured from 740 g (4 mols) of m-bromo-o- Table 3 below sets forth the specific dialkylphenylphenyl-pyridyl methanol which is reacted with thionylbis-imidazole in the presence of an inert inorganic diluent at from 2() C to C to produce the particular dialkylphenyl-phenyl-pyridyl-imidazole methane set forth in Table 2.

Table 3 DiaIkylphenyI-phenylpyridyl-imidazole-methane In the case of Examples 3, 8 and 10, the free base produced is reacted with the appropriate acid, namely,

Table 4 Dialkylphenyl-phcnylpyridyl-methyl-halidc Example No.

l 3 .4-dimethylphenyl-phenyLZ-pyridyl-mcthyl chloride (or bromide) 2 2,4-dimethylphenyl-phenyl2-pyridyl-methyl chloride (or bromide) 3 3.fi-dimethylphcnyl-phcnyl-2-pyridylmcthyl chloride (or bromide) -l 2,d-dimethyIphcnyl-phcnyl-l-pyridyl-methyl chloride (or bromide) 5 3,4-dimcthylphenyl-phcnyl-4pyridyl-methyl chloride (or bromide) 6 2,S-dimethyIphcnyl-phenyl-4-pyridyl-methyl Chloride (or bromide) 7 2.3-dimethylphenyl phenyl-2pyridyl-mcthyl chloride (or bromide) 8 2,3-dimethylphenyl-phenyl-lpyridybmethyl chloride (or bromide) 9 2,fl-dimethylphcnyl-phenyl-4-pyridyl-mcthyl chloride (or bromide) HI J.4-dimethylphenylphcnyl4- 1yridyl-mcthyl chloride (or bromide) In the case of Examples 3, 8 and It), the free base produced is reacted with the appropriate acid, namely, hydrochloric (Example 3) or LS-naphthalene disulfonic (Examples 8 and 10), to produce the corresponding hydrochloride (Example 3) and l,S-naphthalene disulfonate (Examples 8 and l()).

The hydrochloride salt of the compound of Example 7 is produced by reacting the free base (compound of Example 7) with hydrochloric acid.

What is claimed:

l. A compound of the formula or a pharmaceutically acceptable, non-toxic salt thereof wherein R and R are the same or different alkyl of l to 4 carbon atoms.

2. A salt of a compound of claim 1 wherein the salt is selected from the group consisting of the hydrochloride. the hydrobromide, the phosphate, the nitrate, the acetate, the maleate. the succinate, the fumarate, the tartrate. the citrate. the salicylate, the sorbate, the lactate, and the l,S-naphthalene-disulphonate.

3. A compound according to claim 1 wherein the pyridyl moiety is linked to the methane carbon atom at the 2-position.

4. A compound according to claim 1 wherein the pyridyl moiety is linked to the methane carbon atom at the 4-position.

5. A compound according to claim 1 wherein R and R are each methyl.

6. A compound according to claim 1 wherein R is in the 2- or 3-position.

7. A compound according to claim 1 wherein R is in the 3-, 4-, 5- or 6-position.

8. A compound according to claim 3 wherein R is in the 2- or 3-position and R is in the 3-, 4-, 5- or 6- position, but R and R are not both in the 3-position.

9. A compound according to claim 4 wherein R is in the 2- or 3-position and R is in the 3-, 4-, 5- or 6- position, but R and R are not both in the 3-position.

10. A compound according to claim 5 wherein R is in the 2- or 3-position and R is in the 3-, 4-, 5- or 6- position, but R and R are not both in the 3-position.

II. The compound according to claim I which is l- (3,4-dimethylphenyl-phenyl-2-pyridyl )-methylimidazole.

12. The compound according to claim I which is l- (2,4-dimethylphenyl-phenyl-2-pyridyl )-methylimidazole.

13. A compound according to claim I which is l- (2,6-dimethylphenyl-phenyl-2-pyridyl)-methylimidazole or the hydrochloride salt thereof.

l4. The compound according to claim I which is l- (2,4-dimethylphenyl-phenyl-4-pyridyl )-methylimidazole.

, 15. The compound according to claim I which is l (3 ,4-dimethylphenyl-phenyl-4-pyridyl )-methylimidazole.

16. The compound according to claim 1 which is l- (2,5-dimethylphenyl-phenyl-4-pyridyl)-methylimidazole.

17. The compound according to claim I which is l- 2,3-dimethylphenyl-phenyl-Z-pyridyl )-methylimidazole.

18. The compound according to claim 1 which is the hydrochloride salt of l-(2,3-dimethylphenyl-phenyl-2- pyridyl )-methyl-imidazole.

19. The compound according to claim 1 which is the l ,S-naphthalene-disulphonate salt of l-( 2,3- dimethylphenylphenyl-2-pyridyl)-methyl-imidazole.

20. The compound according to claim 1 which is l- (2,3-dimethylphenyl-phenyl-4-pyridyl)-methylimidazole.

21. The compound according to claim I which is l- (3,4-dimethylphenyl-phenyl-4-pyridyl )-methylimidazole or the l,5-naphthalene-disulphonate salt 

1. A COMPOUND OF THE FORMULA
 2. A salt of a compound of claim 1 wherein the salt is selected from the group consisting of the hydrochloride, the hydrobromide, the phosphate, the nitrate, the acetate, the maleate, the succinate, the fumarate, the tartrate, the citrate, the salicylate, the sorbate, the lactate, and the 1,5-naphthalene-disulphonate.
 3. A compound according to claim 1 wherein the pyridyl moiety is linked to the methane carbon atom at the 2-position.
 4. A compound according to claim 1 wherein the pyridyl moiety is linked to the methane carbon atom at the 4-position.
 5. A compound according to claim 1 wherein R1 and R2 are each methyl.
 6. A compound according to claim 1 wherein R1 is in the 2- or 3-position.
 7. A compound according to claim 1 wherein R2 is in the 3-, 4-, 5- or 6-position.
 8. A compound according to claim 3 wherein R1 is in the 2- or 3-position and R2 is in the 3-, 4-, 5- or 6-position, but R1 and R2 are not both in the 3-position.
 9. A compound according to claim 4 wherein R1 is in the 2- or 3-position and R2 is in the 3-, 4-, 5- or 6-position, but R1 and R2 are not both in the 3-position.
 10. A compound according to claim 5 wherein R1 is in the 2- or 3-position and R2 is in the 3-, 4-, 5- or 6-position, but R1 and R2 are not both in the 3-position.
 11. The compound according to claim 1 which is 1-(3,4-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole.
 12. The compound according to claim 1 which is 1-(2,4-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole.
 13. A compound according to claim 1 which is 1-(2,6-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole or the hydrochloride salt thereof.
 14. The compound according to claim 1 which is 1-(2,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole.
 15. The compound according to claim 1 which is 1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole.
 16. The compound according to claim 1 which is 1-(2,5-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole.
 17. The compound according to claim 1 which is 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole.
 18. The compound according to claim 1 which is the hydrochloride salt of 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole.
 19. The compound according to claim 1 which is the 1,5-naphthalene-disulphonate salt of 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole.
 20. The compound according to claim 1 which is 1-(2,3-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole.
 21. The compound according to claim 1 which is 1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole or the 1,5-naphthalene-disulphonate salt thereof. 